This invention relates to a novel gene that activates Fibroblast Growth Factor Receptor 2 (FGFR2).
The fibroblast growth factors (FGFs) are a family of related proteins with roles in mitogenesis, differentiation, wound healing, and organogenesis (Basilico et al. Adv. Cancer Res. 59:115-165, 1992). The biological responses of FGFs are mediated through specific high-affinity receptor tyrosine kinases (Givol and Yayon, FASEB J. 6:3362-3369, 1992). Four distinct classes of fibroblast growth factor receptor (FGFR) that encode structurally related proteins have been identified: FGFR1/Flg, FGFR2/Bek, FGFR3, and FGFR4 (Diome et al., EMBO J. 9:2685-2692, 1990); Miki et al., Science 251:72-75, 1991; Keegan et al., Proc. Natl. Acad. Sci. USA 88:1095-1099, 1991; and Partanen et al., EMBO J. 10:1347-1354, 1992).
Activating mutations (i.e. mutations, leading to highly phosphorylated receptors, that are associated with various cancer states) in transmembrane domains of EGF receptor and FGFR3 were reported in rat leukemia and human achondroplasia, respectively (Ben-Levy et al., J. Biol. Chem. 267:17304-17313, 1992; and Shiang et al., Cell, 78:335-342, 1994). Furthermore, several growth factor receptors have been found to be activated by chromosomal rearrangement in cancer cells (Sawyers et al., Cell 77:171-173, 1994), including EGFR in leukemias, NGFR (TRK) in colon and thyroid carcinomas, HGFR (MET) in gastric carcinomas, RET in thyroid carcinomas, ALK in lymphomas, and PDGFR.beta. in myeloid leukemias.
One chromosomal rearrangement associated with chronic myelomonocytic leukemia was shown to create an expressed fusion between a novel gene sequence, tel, and the tyrosine kinase domain of the growth factor receptor PDGFR.beta. (Golub et al., Cell 77:307-316, 1994). tel appears to be a member of the ets gene family, members of which encode transcription factors. Genes other than growth factor receptors (GFRs), are activated and cause tumorigenesis by gene fusions resulting from chromosomal arrangement. For example, a majority of the cases of chronic myeloma leukemia (CML) contain a chromosornal rearrangement between chromosome 9 and 22 (t(9;22)(q34;q11) that results in a fusion of the oncogene .alpha.-abo, a cytoplasmic kinase, to bcr, which promotes myeloid tumorigenesis and is used as a diagnostic for the malignancy (Bernards et al., Mol. Cell Biol. 7:3231-3236, 1987; and Konopka et al., Proc. Nat'l Acad. Sci. 82:1810-1813, 1985).